Neovascularization occurs when either there is proliferation of blood vessels in tissues that would otherwise not contain or there is a growth of a different kind of blood vessel in a tissue. Unwanted neovascularization is associated with a number of disease conditions, such as that seen to occur with tumor growth or vision loss. One example of undesirable neovascularization in the eye is choroidal neovasculature (CNV) like that found in the “wet” form of age-related macular degeneration (AMD).
AMD causes severe, irreversible vision loss and is the leading cause of blindness in individuals older than 50 years in the Western World. Most patients have the non-neovascular (“dry”) form, characterized by drusen and abnormalities of the retinal pigment epithelium (RPE). Eighty to ninety percent of the severe vision loss due to AMD, however, is attributable to the form characterized by CNV, also called “wet” AMD. In the United States, between 70,000 to 200,000 individuals over the age of 65 develop the neovascular form of AMD every year (Bressler, N. “Submacular surgery: Are randomized trials necessary?” Arch Ophthalmol. 1995;113;1557-1560; Klein, R. et al. “The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study.” Ophthalmol. 1997;104(1):7-21).
In CNV, the newly formed vessels have a tendency to leak blood and fluid, causing symptoms of scotoma and metamorphopsia (Macular Photocoagulation Study Group. “Argon laser photocoagulation for neovascular maculopathy. Three-year results from randomized clinical trials.” Arch Ophthalmol. 1986;104:694-701). The new vessels are accompanied by proliferation of fibrous tissue (Macular Photocoagulation Study Group. “Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration. Updated findings from two clinical trials.” Arch Ophthalmol. 1993;111:1200-1209). This complex of new vessels and fibrous tissue can destroy photoreceptors within 3 to 24 months. At the same time that existing CNV is destroying retinal tissue where it has formed, the lesion can continue to grow throughout the macula, resulting in progressive, severe and irreversible vision loss. Without treatment, most affected eyes will have poor central vision (<20/200) within 2 years (Macular Photocoagulation Study Group. “Recurrent choroidal neovascularization after argon laser photocoagulation for neovascular maculopathy.” Arch Ophthalmol. 1986; 104:503-512). In addition, when one eye of an individual develops CNV, the fellow eye has about a 50% chance of developing a similar CNV lesion within 5 years (Treatment of Age-related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. “Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with VISUDYNE: One-year results of 2 randomized clinical trials—TAP report 1.” Arch Ophthalmol. 1999;117:1329-1345).
Photodynamic therapy (PDT) offers an approach to selectively destroy CNV without significant destruction of overlying retina tissue, possibly by occluding the new vessels within the CNV lesion. Photodynamic therapy is a two-step process consisting of an intravenous injection of a photosensitizer (light-activated drug) followed by light application (Marcus, S. “Photodynamic therapy of human cancer: clinical status, potential and needs.” In: Gomer C, ed. Future Directions and Application In Photodynamic Therapy. Berlingham: SPIE Press. 1990;IS6:5-56; Manyak, M. J. et al. “Photodynamic therapy.” J Clin Oncol. 1988;6:380-391; Roberts, W. G. et al. “Role of neovasculature and vascular permeability on the tumor retention of photodynamic agents.” Cancer Res. 1992;52(4):924-930). The light sources most commonly used are non-thermal lasers or light emitting diodes (LEDs). Photosensitizers may preferentially accumulate in neovascular tissues, including the endothelial cells of choroidal neovascularization. In combination with localized light administration, this allows for selective treatment of the pathologic tissue (Kreimer-Birmbaum, M. “Modified porphyrins, chlorins, phthalocyanines, and purpurins: second generation photosensitizers for photodynamic therapy.” Semin Hematol. 1989;26:157-173; Moan, J. et al. “Photosensitizing efficiencies, tumor and cellular uptake of different Photosensitizing drugs relevant for photodynamic therapy of cancer.” Photochem Photobiol. 1987;46:713-721). After exposure to light at a wavelength of 689 m, an energy transfer cascade is initiated, culminating in the formation of singlet oxygen which generates intracellular free radicals (Kreimer-Birmbaum, M., supra; Roberts, W. G. et al. “In vitro photosensitization I. Cellular uptake and subcellular localization of mono-1-aspartyl chlorin e6, chloro-aluminum sulfonated phthalocyanine, and Photofrin II.” Lasers Surg. Med. 1989;9:90-101; Lear, J. et al. “Low back pain associated with streptokinase.” Lancet. 1992;340:851). These free radicals can disrupt cellular structures such as the cell membrane, mitochondria, and lysosomal membranes (Sculier, J. P. et al. “Intravenous infusion of high doses of liposomes containing NSC 251635, a water insoluble cytostatic agent: A pilot study with pharmacokinetic data.” J Clin Oncol. 1986;4:789-797).
Given the supply of oxygen available from the neovasculature, PDT has been particular effective at destroying CNV, presumably by occluding the neovasculature. Thus relatively high fluency rates of irradiation, such as approximately 600 mW/cm2, have been used to activate the photosensitizer in PDT, with the limit on total light dose (in J/cm2) being set by nonselective closure of retinal blood vessels and the associated vision loss (see Miller et al. Arch. Ophthalmol. 117:1161-1173 (1999)). The currently approved therapy uses 600 mW/cm2 to deliver a total light dose of 50 J/cm2. This therapy has also been found to enhance the visual acuity of treated subjects (see U.S. Pat. No. 5,756,541 for example).
Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.